Although substantial data exist on the pathophysiology of hypoglycemia, relatively less work has examined how human cerebral functional activation is modulated by hypoglycemia. However, developments in vivo MR spectroscopy and functional MRI provide important new avenues to evaluate the metabolic dynamics of functional activation. This application proposes to assess the (patho)physiology of functional activation in euglycemia and hypoglycemia (insulin induced vs. fasting induced), and to examine the effects from ketones. In particular, in this application we hypothesize that ketones can provide substrate for cerebral activation, and to that extent, can be evaluated through the dynamics of lactate generation and extent of fMRI activation. These studies will be performed in both normal control and type 1 diabetic subjects. This is an R21, rather than a RO1 application because although recent data from Amiel et al and Veneman et al have shown that ketones can improve neurological symptomatology and cognitive performance in hypoglycemia, we do not know how ketones contribute to the metabolic physiology of functional activation. In some aspects, the hypothesis of ketones being directly contributing to functional activity is risky, because of the models suggesting that glucose is an obligate fuel. However, much existing imaging data (PET and MR) can be consistent with the view that oxidation is an important component of cerebral activation. We believe that this proposal will provide data to determine the potential role for ketones in hypoglycemia both in normal subjects and in type 1 diabetes mellitus (T1 DM) since we believe that the problem of cerebral hypoglycemia in T1DM relates in part to how the brain is able (or not) to draw on alternate fuels in activation. Work from this proposal will provide new information that may significantly change the perception as to how the brain works, as well as provide impetus towards development of ketones as an option in the clinical management of hypoglycemia.